EP2917171B1 - Process for preparation of mk-7 type of vitamin k2 - Google Patents

Process for preparation of mk-7 type of vitamin k2 Download PDF

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Publication number
EP2917171B1
EP2917171B1 EP13792773.7A EP13792773A EP2917171B1 EP 2917171 B1 EP2917171 B1 EP 2917171B1 EP 13792773 A EP13792773 A EP 13792773A EP 2917171 B1 EP2917171 B1 EP 2917171B1
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EP
European Patent Office
Prior art keywords
formula
phenylsulfonyl
yield
derivative
group
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EP13792773.7A
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German (de)
English (en)
French (fr)
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EP2917171A2 (en
Inventor
Krzysztof Krajewski
Andrzej Kutner
Jadwiga Dzikowska
Regina Gutowska
Marek NAPIÓRKOWSKI
Jerzy Winiarski
Marek Kubiszewski
Lukasz Jedynak
Jacek MORZYCKI
Stanislaw Witkowski
Aneta BAJ
Piotr Walejko
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Nattopharma R&D Ltd
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Nattopharma R&D Ltd
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Priority to PL13792773T priority Critical patent/PL2917171T3/pl
Publication of EP2917171A2 publication Critical patent/EP2917171A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
    • C07C49/553—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation

Definitions

  • MK-7 type of vitamin K 2 is characterized by better bioavailability and efficacy than the other vitamins K. It is also characterized by the high absorption in small intestine and sustained presence in a blood serum (up to 3 days). Even small daily doses of vitamin MK-7 are sufficient to provide all cells and tissues with vitamin K dependent enzymes and proteins at the proper level. On account of participation in calcium metabolism, vitamin MK-7 is indirectly involved in strong bones formation. Unlike vitamin K 1 , it also influences arterial vessel wall condition.
  • Example 6 synthesis of pentaprenyl alcohol from diprenyl-alcohol bromide, having protected acetyl and phenylsulfonyltriprenyl groups, is described. After each step of the process: alkylation, desulfonylation and removal of hydroxyl protecting groups, purification of the product by silica gel flash chromatography is necessary. Polyprenyl halides obtained according to this procedure have been used in the vitamins K 2 synthesis, in particular vitamin MK-7 synthesis, under Grignard/Kumada or Suzuki conditions, following "0+7" or "2+5" strategy.
  • Min et al. J. Org. Chem. 2003, 68, 7925-7927 ) describe the Friedel-Crafts allylation of a prenyl group stabilized by a sulfone moiety.
  • the reference further relates to the synthesis of ubiquinones and menaquinones from the resulting protected p-hydroquinone containing the C 5 trans-allylic sulfone moiety.
  • the key step in the preparation of vitamin MK-7 according to the present invention is coupling of the A and B synthons, accomplished due to the nucleophilic addition.
  • oxidation can be performed using stoichiometric amount of SeO 2 , or preferably, catalytic amount of SeO 2 using acid as co-catalyst, for example salicylic acid or SiO 2 , in presence of 2-3-fold molar excess of co-oxidizer, such as tert -butyl peroxide (in water or organic solvent) or hydrogen peroxide.
  • co-oxidizer such as tert -butyl peroxide (in water or organic solvent) or hydrogen peroxide.
  • oxidation reaction can be accomplished using SeO 2 in the presence of molar excess of N -oxide N -methylmorpholine.
  • hexaprenol derivative of formula (VI) is converted into hexaprenyl bromide of formula (VII) in the reaction with PBr 3 .
  • the compound of the formula (IX) is subjected to oxidative deeteryfication, to restore the quinine structure of the starting menadione.
  • vitamin MK-7 is obtained in unexpectedly high yield and in one step shorter process, which effects in reduction of time and expensive reagents consumption. Moreover, the total amount of both "migration-type” (ie. formed as a result of the double bonds migration along the heptaprenyl chain) and " cis " impurities, which tends to be formed in desulfonation step, could be substantially reduced.
  • E , E -Farnesyl acetate was purified by column chromatography using ethyl acetate/hexane (2:98) as eluent to obtain pale yellow oil (5.62 g, 21 mmol, 95%).
  • reaction vessel (2,5 L capacity) equipped with CaCl 2 tube, thermocouple, mechanic stirrer, nitrogen line adapter, immersed in a cooling bath (acetone / CO 2 ), the mixture of sulfone VIA (57.36 g) and THF (400 mL) was stirred under N 2 for 5 min, and then cooled to 0°C. A this temperature, Pd(dppe)Cl 2 catalyst (1.75 g) was added, followed by dropwise addition of 1 M LiEt 3 BH (303 ml) within 40 min. Reaction progress was monitored by TLC. After 30 min.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP13792773.7A 2012-10-12 2013-10-11 Process for preparation of mk-7 type of vitamin k2 Active EP2917171B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PL13792773T PL2917171T3 (pl) 2012-10-12 2013-10-11 Sposób wytwarzania witaminy K<sub>2</sub> w formie MK-7

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PL401195A PL401195A1 (pl) 2012-10-12 2012-10-12 Sposób wytwarzania witaminy K2 w formie MK-7
US201361771741P 2013-03-01 2013-03-01
PCT/PL2013/000132 WO2014058330A2 (en) 2012-10-12 2013-10-11 Process for preparation of mk-7 type of vitamin k2

Publications (2)

Publication Number Publication Date
EP2917171A2 EP2917171A2 (en) 2015-09-16
EP2917171B1 true EP2917171B1 (en) 2018-11-07

Family

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Family Applications (1)

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EP13792773.7A Active EP2917171B1 (en) 2012-10-12 2013-10-11 Process for preparation of mk-7 type of vitamin k2

Country Status (19)

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US (1) US9828323B2 (es)
EP (1) EP2917171B1 (es)
JP (1) JP2015531404A (es)
KR (1) KR102229841B1 (es)
CN (1) CN104903282B (es)
AU (1) AU2013330517B2 (es)
BR (1) BR112015008021A2 (es)
CA (1) CA2888010C (es)
CY (1) CY1121117T1 (es)
DK (1) DK2917171T3 (es)
ES (1) ES2701808T3 (es)
IL (1) IL238199A (es)
LT (1) LT2917171T (es)
MX (1) MX2015004618A (es)
PL (2) PL401195A1 (es)
RU (1) RU2015117398A (es)
TN (1) TN2015000137A1 (es)
TR (1) TR201818397T4 (es)
WO (1) WO2014058330A2 (es)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0817528D0 (en) 2008-09-24 2008-10-29 Syntavit As Process
PL424875A1 (pl) * 2018-03-12 2019-09-23 Vitasynth Spółka Z Ograniczoną Odpowiedzialnością Sposób syntezy witaminy K2
US11407704B2 (en) 2018-04-06 2022-08-09 Siec Badawcza Lukasiewicz-Instytut Chemii Przemyslowej Imienia Profesora Ignacego Moscickiego Process of vitamin K2 derivatives preparation
WO2021071372A1 (en) 2019-10-07 2021-04-15 Sieć Badawcza Łukasiewicz - Instytut Farmaceutyczny Process of vitamin k2 derivatives preparation
PL243187B1 (pl) 2020-07-16 2023-07-10 Vitasynth Spolka Z Ograniczona Odpowiedzialnoscia Sposób i związki pośrednie do otrzymywania menachinonu MK-7
CN113403348B (zh) * 2021-06-18 2022-03-22 山东润德生物科技有限公司 一种维生素k2的制备方法
WO2023031841A1 (en) * 2021-09-03 2023-03-09 Synergia Life Sciences Pvt. Ltd. A process for the stereospecific synthesis of vitamin k2 and its intermediates
CN114149314B (zh) * 2021-11-26 2024-05-28 安徽先和医药研究有限公司 Vk2的合成方法
WO2024013633A1 (en) * 2022-07-11 2024-01-18 Synergia Life Sciences Pvt. Ltd. Process for the synthesis of vitamin k2
CN117867044B (zh) * 2023-12-27 2024-07-30 杭州微远生物科技有限公司 一种维生素mk-4的生物酶法制备工艺

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4199531A (en) 1976-10-19 1980-04-22 Takeda Chemical Industries, Ltd. Intermediates for the production of quinones
WO2010035000A1 (en) * 2008-09-24 2010-04-01 Kappa Bioscience As Process for the preparation of vitamin k2
WO2011117324A2 (en) 2010-03-23 2011-09-29 Kappa Bioscience As Process for the preparation of vitamin k2

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2435466A1 (fr) * 1978-08-02 1980-04-04 Kuraray Co Derives de l'hydroquinone et leur procede de preparation
US8414565B2 (en) * 2002-12-16 2013-04-09 The Ohio State University Parametric model based ablative surgical systems and methods
FR2925908A1 (fr) * 2007-12-27 2009-07-03 Bmuestar Silicones France Sas Composition reticulable/polymerisable par voie cationique comprenant un borate de iodonium et degageant une odeur acceptable
DE202008008134U1 (de) 2008-06-17 2009-06-25 Bischof + Klein Gmbh & Co. Kg Seitenfaltenbeutel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4199531A (en) 1976-10-19 1980-04-22 Takeda Chemical Industries, Ltd. Intermediates for the production of quinones
WO2010035000A1 (en) * 2008-09-24 2010-04-01 Kappa Bioscience As Process for the preparation of vitamin k2
WO2011117324A2 (en) 2010-03-23 2011-09-29 Kappa Bioscience As Process for the preparation of vitamin k2

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Acetoxy", WIKIPEDIA, THE FREE ENCYCLOPEDIA, 2 September 2018 (2018-09-02), XP055628602, Retrieved from the Internet <URL:https://en.wikipedia.org/wiki/Acetoxy_ group>
ANONYMOUS: "Geraniol", WIKIPEDIA, THE FREE ENCYCLOPEDIA, 5 July 2019 (2019-07-05), XP055628605, Retrieved from the Internet <URL:https://en.wikipedia.org/wiki/Geraniol>
ANONYMOUS: "Geranylfarnesol - CAS 22488-05-7", BOC SCIENCES, 2019, XP055628616, Retrieved from the Internet <URL:https://www.bocsci.com/geranylfarnesol-cas-22488-05-7-item-485434.html>
JAE-HONG MIN ET AL.: "The Friedel-Crafts Allylation of a Prenyl Group Stabilized by a Sulfone Moiety: Expeditious Syntheses of Ubiquinones and Menaquinones", J. ORG. CHEM., vol. 68, no. 20, January 2003 (2003-01-01), pages 7925 - 7927, XP002342639
MIN J-H ET AL: "Supporting information: The Friedel-Crafts Allylation of a Prenyl Group Stabilized by a Sulfone Moiety: Expeditious Syntheses of Ubiquinones and Menaquinones", JOURNAL OF ORGANIC CHEMISTRY, vol. 68, no. 20, January 2003 (2003-01-01), XP055628599
YUKIO MASAKI ET AL.: "Synthetic Studies on Isoprenoidquinones. II.1l Syntheses of Ubiquinone-10, Phylloquinone, and Menaquinone-4 by a Chain-Extending Method Utilizing Terminally Functionalized Isoprenoidhydroquinones", CHEM. PHARM. BULL., vol. 32, no. 10, January 1984 (1984-01-01), pages 3959 - 3967, XP008057512

Also Published As

Publication number Publication date
JP2015531404A (ja) 2015-11-02
AU2013330517A1 (en) 2015-05-28
KR20150091469A (ko) 2015-08-11
DK2917171T3 (en) 2019-01-07
PL401195A1 (pl) 2014-04-14
AU2013330517B2 (en) 2017-07-20
KR102229841B1 (ko) 2021-03-22
IL238199A (en) 2017-04-30
TR201818397T4 (tr) 2019-01-21
CY1121117T1 (el) 2019-12-11
PL2917171T3 (pl) 2019-04-30
US20150291498A1 (en) 2015-10-15
CN104903282B (zh) 2018-10-23
US9828323B2 (en) 2017-11-28
WO2014058330A3 (en) 2014-06-19
WO2014058330A2 (en) 2014-04-17
EP2917171A2 (en) 2015-09-16
MX2015004618A (es) 2016-06-10
TN2015000137A1 (en) 2016-10-03
CN104903282A (zh) 2015-09-09
BR112015008021A2 (pt) 2017-07-04
CA2888010A1 (en) 2014-04-17
ES2701808T3 (es) 2019-02-26
RU2015117398A (ru) 2016-11-27
CA2888010C (en) 2021-05-25
LT2917171T (lt) 2019-01-25

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